Alterations of Sleep and Sleep Oscillations in the Hemiparkinsonian Rat

Our previous studies in the rat model of Parkinson’s disease (PD) cholinopathy demonstrated the sleep-related alterations in electroencephalographic (EEG) oscillations at the cortical and hippocampal levels, cortical drives, and sleep spindles (SSs) as the earliest functional biomarkers preceding hypokinesia. Our aim in this study was to follow the impact of a unilateral substantia nigra pars compacta (SNpc) lesion in rat on the cortical and hippocampal sleep architectures and their EEG microstructures, as well as the cortico-hippocampal synchronizations of EEG oscillations, and the SS and high voltage sleep spindle (HVS) dynamics during NREM and REM sleep. We performed unilateral SNpc lesions using two different concentrations/volumes of 6-hydroxydopamine (6-OHDA; 12 μg/1 μl or 12 μg/2 μl). Whereas the unilateral dopaminergic neuronal loss >50% throughout the overall SNpc rostro-caudal dimension prolonged the Wake state, with no change in the NREM or REM duration, there was a long-lasting theta amplitude augmentation across all sleep states in the motor cortex (MCx), but also in the CA1 hippocampus (Hipp) during both Wake and REM sleep. We demonstrate that SS are the hallmarks of NREM sleep, but that they also occur during REM sleep in the MCx and Hipp of the control rats. Whereas SS are always longer in REM vs. NREM sleep in both structures, they are consistently slower in the Hipp. The dopaminergic neuronal loss increased the density of SS in both structures and shortened them in the MCx during NREM sleep, without changing the intrinsic frequency. Conversely, HVS are the hallmarks of REM sleep in the control rats, slower in the Hipp vs. MCx, and the dopaminergic neuronal loss increased their density in the MCx, but shortened them more consistently in the Hipp during REM sleep. In addition, there was an altered synchronization of the EEG oscillations between the MCx and Hipp in different sleep states, particularly the theta and sigma coherences during REM sleep. We provide novel evidence for the importance of the SNpc dopaminergic innervation in sleep regulation, theta rhythm generation, and SS/HVS dynamics control. We suggest the importance of the underlying REM sleep regulatory substrate to HVS generation and duration and to the cortico-hippocampal synchronizations of EEG oscillations in hemiparkinsonian rats

An electrochemical illustration of the mathematical modelling of chlorine impact and acidification in electrochemical tumour treatment and its application on an agar-agar gel system

Electrochemical treatment (EchT) of tumours, which is also known as electrochemical therapy, implies that tumour tissue is treated with a direct current through the use of electrodes. This was shown earlier when the major electrochemical reactions at the anode were chlorine and oxygen evolution and the impact of chlorine in EchT was investigated by mathematical modelling. In this work the electrochemical illustration of a mathematical model of electrochemical treatment of tumours is presented using a Pt electrode placed in agar-agar gel containing 1% phenolphthalein and NaCl. The appearance of the bright red color around the Pt wire due to the pH change caused by hydrogen evolution is used for the simulation of the shape and the boundaries of the tumour tissue. After the polarity was changed, oxygen evolution takes place on the Pt wire electrode and the red color disappears simulating the destructive influence of the electrochemical process on tumour tissue. A better understanding of the mathematical model presented earlier is achieved and it can be used for educational purposes in oncological praxis because agar-agar is the closest approximation to the ground substance of connective human tissue and successfully simulates the processes which occur in vivo. There is also some quantitative agreement between the results calculated earlier and those obtained in this work. The previous model was based on tissue, which was treated as an aqueous solution of sodium chloride containing bicarbonate and proteins and the results presented a detailed and useful quantitative analysis of the system. In this work, the quantitative analysis presented is based on an agar-agar system and the experimental conditions give the possibility of more detailed qualitative analysis. The combination of these two models offers a better simulation of the processes in vivo

Corticosterone and Glucocorticoid Receptor in the Cortex of Rats during Aging—The Effects of Long-Term Food Restriction

Numerous beneficial effects of food restriction on aging and age-related pathologies are well documented. It is also well-established that both short- and long-term food restriction regimens induce elevated circulating levels of glucocorticoids, stress-induced hormones produced by adrenal glands that can also exert deleterious effects on the brain. In the present study, we examined the effect of long-term food restriction on the glucocorticoid hormone/glucocorticoid receptor (GR) system in the cortex during aging, in 18- and 24-month-old rats. Corticosterone level was increased in the cortex of aged ad libitum-fed rats. Food restriction induced its further increase, accompanied with an increase in the level of 11β-hydroxysteroid dehydrogenase type 1. However, alterations in the level of GR phosphorylated at Ser232 were not detected in animals on food restriction, in line with unaltered CDK5 level, the decrease of Hsp90, and an increase in a negative regulator of GR function, FKBP51. Moreover, our data revealed that reduced food intake prevented age-related increase in the levels of NFκB, gfap, and bax, confirming its anti-inflammatory and anti-apoptotic effects. Along with an increase in the levels of c-fos, our study provides additional evidences that food restriction affects cortical responsiveness to glucocorticoids during aging

Short-Term Fish Oil Treatment Changes the Composition of Phospholipids While Not Affecting the Expression of Mfsd2a Omega-3 Transporter in the Brain and Liver of the 5xFAD Mouse Model of Alzheimer’s Disease

Long-term fish oil (FO) supplementation is able to improve Alzheimer’s disease (AD) pathology. We aimed to determine the impact of short-term fish oil (FO) intake on phospholipids composition and plaque pathology in 5xFAD mice, a widely used animal model of AD. A 3-week-long FO supplementation administered at 3 months of age decreased the number of dense core plaques in the 5xFAD cortex and changed phospholipids in the livers and brains of wild-type (Wt) and 5xFAD mice. Livers of both genotypes responded by increase of n-3 and reciprocal decrease of n-6 fatty acids. In Wt brains, FO supplementation induced elevation of n-3 fatty acids and subsequent enhancement of n-6/n-3 ratio. However, in 5xFAD brains the improved n-6/n-3 ratio was mainly due to FO-induced decrease in arachidonic and adrenic n-6 fatty acids. Also, brain and liver abundance of n-3 fatty acids were strongly correlated in Wts, oppositely to 5xFADs where significant brain-liver correlation exists only for n-6 fatty acids. Expression of omega-3 transporter Mfs2a remained unchanged after FO supplementation. We have demonstrated that even a short-term FO intake improves the phospholipid composition and has a significant effect on plaque burden in 5xFAD brains when applied in early stages of AD pathology

Long-term intermittent feeding restores impaired GR signaling in the hippocampus of aged rat

Diminished glucocorticoid signaling is associated with an age-related decline in hippocampal functioning. In this study we demonstrate the effect of intermittent, every other day (EOD) feeding on the glucocorticoid hormone/glucocorticoid receptor (GR) system in the hippocampus of middle-aged (18-month-old) and aged (24-month-old) Wistar rats. In aged ad libitum-fed rats, a decrease in the level of total GR and GR phosphorylated at Ser(232) (pGR) was detected. Conversely, aged rats subjected to EOD feeding, starting from 6 months of age, showed an increase in GR and pGR levels and a higher content of hippocampal corticosterone. Furthermore, prominent nuclear staining of pGR was observed in CM pyramidal and DG granule neurons of aged EOD-fed rats. These changes were accompanied by increased Sglc-1 and decreased GFAP transcription, pointing to upregulated transcriptional activity of GR. EOD feeding also induced an increase in the expression of the mineralocorticoid receptor. Our results reveal that intermittent feeding restores impaired GR signaling in the hippocampus of aged animals by inducing rather than by stabilizing GR signaling during aging. (C) 2015 Elsevier Ltd. All rights reserved.Ministry of Education, Science and Technological Development of the Republic of Serbia {[}ON173056, ON173008]; NIH {[}R03AG046216

The effects of dietary restriction and aging on amyloid precursor protein and presenilin-1 mRNA and protein expression in rat brain

The objective of this study was to examine the effects of aging and long-term dietary restriction (DR) on the level of amyloid precursor protein (APP) and presenilin-1 (PS-1), proteins that are critically involved in Alzheimer's disease. Changes in mRNA and protein expression were assessed by real-time PCR and western blot analysis during aging and long-term DR in the cortex and hippocampus of 6-, 12-, 18-, and 24-month-old rats. Prominent regional changes in expression were observed in response to aging and DR. Although the hippocampus displayed significant alterations in APP mRNA and protein expression and no significant changes in PS-1 expression, an opposite pattern was observed in the cortex. DR counteracted the age-related changes in APP mRNA expression in both structures of old animals. The observed DR-induced increase in mRNA levels in the hippocampus was accompanied by an increase in the level of full-length protein APP. These results indicate that although both structures are very sensitive to aging, a specific spatial pattern of changes in APP and PS-1 occurs during aging. Furthermore, these findings provide evidence that DR can affect APP and PS-1 expression in a manner consistent with its proposed `antiaging' effect.Ministry of Education, Science and Technological Development of the Republic of Serbia {[}173056

Anthraquinone-chalcone hybrids: Synthesis, preliminary antiproliferative evaluation and DNA-interaction studies

Novel anthraquinone based chalcone compounds were synthesized starting from 1-acetylanthraquinone in a Claisen-Schmidt reaction and evaluated for their anticancer potential against three human cancer cell lines. Compounds 4a, 4b and 4j showed promising activity in inhibition of HeLa cells with IC50 values ranging from 2.36 to 2.73 mu M and low cytotoxicity against healthy MRC-5 cell lines. The effects that compounds produces on the cell cycle were investigated by flow cytometry. It was found that 4a, 4b and 4j cause the accumulation of cells in the S and G2/M phases in a dose-dependent manner and induce caspase-dependent apoptosis. All of three compounds exhibit calf thymus DNA-binding activity. The determined binding constants by absorption titrations (2.65 x 10(3) M-1, 1.36 x 10(3) M(-1)and 2.51 x 10(3) M-1 of 4a/CT-DNA, 4b/CT-DNA and 4j/CT-DNA, respectively) together with fluorescence displacement analysis designate 4a, 4b and 4j as strong minor groove binders, but no cleavage of plasmid DNA was observed